Stroke

Question 1

Etiology of stroke

Answer 1

. Cardiovascular risk factors alter the vessel wall and inc. likelihood of cerebrovascular event
. Inc. oxidative stress is an early change which dampens NO production by endothelial cells
. Endothelial cells inc. production of local mediators that modulate vessel tone and promote development and progression of atherosclerosis
. Actions of cells progress thrombosis/embolism, inflammation, vasocontriction and vascular remodeling
. Presence of risk factors begins a progression that sets the stage for stroke

Question 2

Types of ischemic stroke

Answer 2

. Focal: occlusion of specific cerebral vessel resulting in loss of blood flow to that region and subsequent tissue death
. Global: drastic reduction in systemic bp that produces general ischemia in brain

Question 3

Causes of ischemic stroke

Answer 3

. Thrombosis: localized occlusion of cerebral vessel
. Embolism: part of clot that dislodges from its original location and can travel through circulation and block a cerebral vessel
. Hypoperfusion: reduction in blood flow to all parts of body due to heart failure

Question 4

Types of hemorrhagic stroke

Answer 4

. Intracerebral: intra-axial hemorrhage where blood accumulates inside brain
. Intraparenchymal: bleeding w/in brain tissues
. Intraventricular: bleeeding in ventricular system
. Epidural hematoma: btw dura and cranium
. Subdural hematoma: btw dura and arachnoid
. Subarachnoid: btw arachnoid and pia

Question 5

Effects of decrease in cerebral blood flow in focal ischemia

Answer 5

. lower CBF causes decline in ATP, glucose, and pH

. Decrease in apparent diffusion coefficient (ADC) in extracellular space which measures inc. swelling

Question 6

Thresholds of CBF

Answer 6

. Normal: 50-60 mL/100g/min
. Oligemia: 20-40
. Ischemia: under 20
. Impairment of electrical and synaptic activity below 20
. Irreversible neuronal injury when less than 10

Question 7

Core infarct

Answer 7

. 10 mL/100g/min is threshold for development
. Centra area characterized by cell death from localized lack of oxygen
. W/in 1 hour after ischemic event the core infarct is surrounded by an oligemic zone called penumbra

Question 8

Critical time period for stroke

Answer 8

2 to 4 hours

Question 9

Glutamate excitotoxicity

Answer 9

. Overexcitation of neurons in response to AA NTs
. Depleting of cellular energy stores triggers release of Glu from synaptic vesicles which activate Glu receptors (NMDA and AMPA)
. Activation of receptors mediates influx of ions (Na and Ca)

Question 10

Peri-infarct/spreading depolarization

Answer 10

. W/in core, neurons can depolarize due to reduced ATP levels and release K and Glu and never repolarize and then depolarize again
. Repetitive depolarization are peri-infarcts
. As number of depolarization inc. the larger the infarcts grow

Question 11

Effect of Ca homeostasis disruption on neurons

Answer 11

. Intracellular Ca activates a series of destructive enzymes that produce inflammation that damages membranes and organelles

Question 12

Edema during ischemic stroke

Answer 12

. Causes secondary damage by inc. intracranial pressure
. Vasogenic edema caused by inc. ECF due to inc. permeability or breakdown of BBB
. Cytotoxic edema is from failure of energy-driven transport of Na and Ca which results in swelling of neurons and glia

Question 13

Inflammation in ischemic stroke

Answer 13

. Initiated by rapid production of inflammation mediators and leukocyte recruiting as a early as 30 min after
. Mediators promote vasodilation/constriction, inc. permeability, and platelet aggregation
. Red neurons (eosinophilia neurons) result from early ischemic injury
. After 6-12 hrs the nucleus is shriveled, hyperchromatic and pyknotic
. Loss of demarcation new white and gray matter from tissue destruction by proteases
. Fluid-filled cysts in later stages, tissue is removed by macrophages and cysts have dark gray margin representing gliosis

Question 14

Goal of therapeutics for stroke

Answer 14

Limit size of penumbra
. Done via neuroprotection (Glu receptor antagonists, Ca channel inhibitors, Free radical scavengers) or vascular agents (clot dissolver, anticoagulants, antiplatelet agents)

Question 15

Glu receptor antagonists

Answer 15

. Reduce spreading of depolarizations, infarct volume, and neurological deficits in focal ischemia
. Use was discontinued in clinical rials bc of adverse effects and potential neurotoxicity

Question 16

Ca channel inhibitors

Answer 16

. Reduce infarct size when introduced shortly after focal ischemia
. Less potent than Glu receptor antagonists
. No benefits in stroke trials, only on animal models

Question 17

Free radical scavengers

Answer 17

. May elicit protection by inc. intracellular glutathione levels
. Show some neurological improvements at early time points but not effective later

Question 18

Clot dissolvers

Answer 18

. Thrombolytic agents that break down clots
. Use tissue plasminogen activator (TPA) in acute ischemic stroke
. Must be administered w/in 4.5 hrs of ischemic event
. Beyond that harm outweighs benefits

Question 19

Anticoagulants

Answer 19

. Reduce stroke frequency

. Only partially effective in preventing recurrence of stroke

Question 20

Antiplatelet agents

Answer 20

. Prevent platelet aggregation and clot formation

. Patients w/ cardiovascular disease often give low dose aspirin

Question 21

Reasons for failure of clinical trials

Answer 21

. Timing of drug administration
. Simulating a model of age and assoc. illness
. Validity of cell culture and animal models
. Inherent drug toxicity
. Different observed efficacious in animal SBS. Humans
. Challenge of getting drugs effectively in brain
. Highly variable in humans